Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study

Abstract Objective To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. Design Population based matched cohort study. Setting Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. Population Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling. Main outcome measures The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding. Results Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%). Conclusions Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.


Introduction
Dementia is a clinical syndrome characterised by progressive cognitive decline and functional disability, with estimates suggesting that by 2050 around 152.8 million people globally will be affected. 1Behavioural and psychological symptoms of dementia are common aspects of the disease and include features such as apathy, depression, aggression, anxiety, irritability, delirium, and psychosis.5][6] During the covid-19 pandemic, the proportion of people with dementia prescribed antipsychotics increased, possibly owing to worsened behavioural and psychological symptoms of dementia linked to lockdown measures or reduced availability of non-pharmaceutical treatment options. 7According to guidelines from the UK's National Institute for Health and Care Excellence, antipsychotics should only be prescribed for the treatment of behavioural and psychological symptoms of dementia if nondrug interventions have been ineffective, if patients are at risk of harming themselves or others or are experiencing agitation, hallucinations, or delusions causing them severe distress. 8Antipsychotics should at most be prescribed at the lowest effective dose and for the shortest possible time.Only two antipsychotics, risperidone (an atypical, or second generation, antipsychotic) and haloperidol (a typical, or first generation, antipsychotic), are licensed in the UK for the treatment of behavioural and psychological symptoms of dementia, 9 although others have been commonly prescribed off-label. 5 10ased on evidence from clinical trials of risperidone, the US Food and Drug Administration (FDA) first issued a warning in 2003 about the increased risks of cerebrovascular adverse events (eg, stroke, transient ischaemic attack) associated with use of atypical antipsychotics in older adults with dementia. 11A metaanalysis of 17 trials among such patients subsequently found a 1.6-1.7-foldincreased risk of mortality with atypical antipsychotics compared with placebo, which led the FDA to issue a "black box" warning in 2005 for all atypical antipsychotics. 11][14] The increased risks for stroke and mortality have been consistently reported by many observational studies and meta-analyses since, 11 15-21 and they have led to regulatory safety warnings and national interventions in the UK, US, and Europe, aiming to reduce inappropriate prescribing of these drugs for the treatment of behavioural and psychological symptoms of dementia. 8 11 22-26Other adverse outcomes have also been investigated in observational studies, [27][28][29] although, with the exception of pneumonia, 14 30-32 the evidence is less conclusive or is more limited among people with dementia.5][46] Most studies also reported only one outcome or type of outcomes.Examining multiple adverse events in a single cohort is needed to give a more comprehensive estimate of the total potential harm associated with use of antipsychotics in people with dementia.
Using linked primary and secondary care data in England, we investigated the risks of a range of adverse outcomes potentially associated with antipsychotic use in a large cohort of adults with dementianamely, stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury.We report both relative and absolute risks.

Data sources
The study used anonymised electronic health records from Clinical Practice Research Datalink (CPRD).In the UK, residents are required to be registered with a primary care general practice to receive care from the NHS.The NHS is a publicly funded healthcare service, free at the point of use.More than 98% of the UK population are registered with a general practice, and their electronic health records are transferred when they change practice. 47 48Community prescribing is most often done by the general practitioner, including antipsychotic treatment recommended by specialists.CPRD data are sourced from more than 2000 general practices covering around 20% of the UK population, and include information on diagnoses, primary healthcare contacts, prescribed drugs, laboratory test results, and referrals to secondary healthcare services. 47 48CPRD contains two databases: Aurum and GOLD.CPRD Aurum includes data from contributing general practices in England that use the EMIS Web patient management software, and CPRD GOLD consists of patient data from practices across all four UK nations that use the Vision system.8][49] Primary care data from general practices in England can be linked to other datasets, including hospital admissions in Hospital Episode Statistics, and mortality and index of multiple deprivation data from the Office for National Statistics (ONS).Individual patients can opt-out of sharing their records with CPRD, and individual patient consent was not required as all data were deidentified.

Study population
We delineated two cohorts, one each from Aurum and GOLD.For the latter, we included patients from English practices only because linkage to hospital admission and mortality data were required in our analyses.To ensure that the study dataset would not contain any duplicate patient records, we used the bridging file provided by CPRD to identify English practices that have migrated from the GOLD to the Aurum dataset, and removed such practices from the GOLD dataset.For both cohorts, we included patients who had a first dementia diagnosis code between 1 January 1998 and 31 May 2018.Dementia was identified from Read, SNOMED, or EMIS codes used in the databases (see supplementary appendix).We defined the date of first dementia diagnosis as the date of first dementia code.Patients needed to be aged 50 years or over at the time of dementia diagnosis, have been registered with the CPRD practice for at least a year, not be prescribed an antipsychotic in the 365 days before their first dementia code, and have records that were eligible for linkage to Hospital Episodes Statistics, mortality, and index of multiple deprivation data.In addition, because anticholinesterases (such as donepezil, rivastigmine, and galantamine) may sometimes be prescribed to patients showing signs of dementia before their first dementia code, we excluded patients with an anticholinesterase prescription before their first dementia code.Supplementary figures S1 and S2 show how the two cohorts for Aurum and GOLD, respectively, were delineated.

Study design
Matched cohort design-We implemented a matched cohort design.Supplementary figure S3 shows the study design graphically. 50For the Aurum and GOLD cohorts separately, patients who used antipsychotics were defined as patients in each cohort issued with an antipsychotic prescription after (or on the same day as) the date of their first dementia diagnosis, with the date of first antipsychotic prescription being the index date after which outcomes were measured.For each outcome, follow-up began from the date of the first antipsychotic prescription (the index date) and ended on the earliest of date of first diagnosis of outcome (ie, the earliest recording of the outcome whether it was from the patient's primary or secondary care or mortality records), death, transfer out of the general practice, last data collection date of the general practice, two years from the date of antipsychotics initiation, or 31 May 2018.Because patients who have experienced an outcome were potentially at higher risk of subsequently experiencing the same event, which could confound any risks associated with antipsychotic use, we excluded those with a history of the specific outcome under investigation before the index date from the analysis of that outcome.For example, we excluded patients with a record of stroke before the index date from the analysis of stroke, but they would still be eligible for the study of other outcomes.For the analysis of acute kidney injury, patients with a diagnosis of end stage kidney disease before the index date were also excluded, and a diagnosis of end stage kidney disease after the index date was an additional condition for end of follow-up. 44atched comparators-Each patient who used antipsychotics on or after the date of their first dementia diagnosis was matched using incidence density sampling with up to 15 randomly selected patients who had the same date of first dementia diagnosis (or up to 56 days after) and who had not been prescribed an antipsychotic before diagnosis.Incidence density sampling involves matching on sampling time, with each antipsychotic user in our study being matched to one or more comparators who were eligible for an antipsychotic but had not become a user at the time of matching. 51The selection of comparators was done with replacement-that is, an individual could be used as a comparator in multiple matched sets.In our study, this meant that patients were eligible to be a non-user matched comparator up to the date of their first antipsychotic prescription.We excluded matched comparators with a history of the specific outcome under investigation before the index date from the analysis of that event.For each outcome, follow-up of matched comparators began on the same day as the patient to whom they were matched (the index date) and ended on the earliest of date of their first antipsychotic prescription (if any), or date of one of the end of follow-up events described earlier for the antipsychotic users.

Use of antipsychotics
We included both typical and atypical antipsychotics, identified by product codes in Aurum and GOLD (see supplementary appendix for list of drugs included).
Senior author DMA (pharmacist) reviewed the code lists.As previous studies have shown a temporal association between antipsychotic use and development of adverse outcomes, 30 31 52 we treated use of antipsychotics as a time varying variable, classified as current, recent, and past use.Current use was defined as the first 90 days from the date of an antipsychotic prescription, recent use as up to 180 days after current use ended, and past use as the time after the recent use period had ended.If a patient was issued another prescription during the 90 days after their last prescription, their current use period would be extended by 90 days from the date of their latest prescription.For example, if a patient had two prescriptions and the second was issued 60 days after the first, their current use period would be a total of 150 days: 60 days after the first prescription plus 90 days after the second.At the end of the 150 days current use period, the next 180 days would be the recent use period, and the time after this recent use period would be past use.As patients could have multiple prescriptions over time, they could move between the three antipsychotic use categories during follow-up, and they could therefore be defined as current, recent, or past users more than once.See the supplementary appendix for further information on how this definition is applied.
In post hoc analyses, we also investigated typical versus atypical antipsychotics, and specific drug substances: haloperidol, risperidone, quetiapine, and other antipsychotics (as a combined category).

Outcomes
Outcomes were stroke, venous thromboembolism (including deep vein thrombosis and pulmonary embolism), myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury.With the exceptions of pneumonia and acute kidney injury, outcomes were identified by Read, SNOMED, or EMIS codes in the primary care records, and by ICD-10 (international classification of diseases, 10th revision) codes from linked secondary care data from Hospital Episodes Statistics, and cause of death data from the ONS mortality records.For pneumonia and acute kidney injury, we only included those that were diagnosed in hospitals or as a cause of death, ascertained from Hospital Episodes Statistics and ONS data.
We also investigated appendicitis and cholecystitis combined as an unrelated (negative control) outcome to detect potential unmeasured confounding. 53hese outcomes were chosen because evidence of an association with antipsychotic use is lacking from the literature.We identified appendicitis and cholecystitis from Read, SNOMED, EMIS, and ICD-10 codes.Clinicians (BG, AJA, DRM) checked all code lists (see supplementary appendix).

Covariates
We used propensity score methods to control for imbalances in measurable patient characteristics between antipsychotic users and their matched non-users, with personal characteristics, lifestyle, comorbidities, and prescribed drugs included in the propensity score models.A counterfactual framework for causal inference was applied to estimate the average treatment effect adjusting for inverse probability of treatment weights generated from the propensity score models. 54 55Selection of covariates was informed by the literature, based on their potential associations with antipsychotic initiation and study outcomes. 31 34 44 56 57All variables were assessed before the index date (see supplementary figure S3).Variables for personal characteristics included sex, age at dementia diagnosis, age at start of followup, ethnicity, and index of multiple deprivation fifths based on the location of the general practice.Comorbidities were derived as dichotomous variables and included a history of hypertension, types 1 and 2 diabetes mellitus, chronic obstructive pulmonary disease, rheumatoid arthritis, moderate or severe renal disease, moderate or severe liver disease, atrial fibrillation, cancer, and serious mental illness (bipolar disorders, schizophrenia, schizoaffective disorders, and other psychotic disorders).Lifestyle factors included smoking status and alcohol use.Medication covariates were represented as dichotomous indicators, defined by at least two prescriptions for each of the following drugs in the 12 months before the index date: antiplatelets, oral anticoagulants, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, alpha blockers, beta blockers, calcium channel blockers, diuretics, lipid lowering drugs, insulin and antidiabetic drugs, nonsteroidal anti-inflammatory drugs, antidepressants, benzodiazepines, and lithium.We also included the following potential confounders for the investigations of venous thromboembolism and fracture: prescriptions for hormone replacement therapy and selective oestrogen receptor modulators (for venous thromboembolism), 58 59 a history of inflammatory bowel disease (for pneumonia and fracture), 60 61 and prescriptions for immunosuppressants, oral corticosteroids, and inhaled corticosteroids (for pneumonia). 62 63

Statistical analysis
For each patient included in the study, we derived a propensity score representing the patient's probability of receiving antipsychotic treatment.Propensity scores were estimated using multivariable logistic regression, with antipsychotic use as the dependent variable.Predictors included personal characteristics, lifestyle, comorbidities, and prescribed drugs.Patients with missing information on ethnicity, index of multiple deprivation, smoking, or alcohol use were grouped into an unknown category for each of these variables and included in the propensity score models.We used the Hosmer-Lemeshow test and likelihood ratio test to test the fit of the models, and interaction terms were included to improve the model fit. 64The derived scores were used as inverse probability of treatment weights to reweigh the data, balancing the distribution of baseline covariates between antipsychotic users and nonusers (matched comparators)-that is, standardised differences <0.1 after weighting. 65Propensity score models were run for each outcome, and for the Aurum and GOLD cohorts separately.For further information, see the supplementary appendix section on propensity score methods to control for potential confounding.
Analyses for estimating harms were then conducted after combining (appending) the Aurum and GOLD datasets.We used Cox regression survival analyses to estimate the risks of each outcome associated with antipsychotic use relative to the comparator cohort, and we report the results as hazard ratios.Use of an antipsychotic was treated as a time varying variable.To account for the matched design, we fitted stratified models according to the matched sets and used robust variance estimation.In all models, we also included a covariate indicating whether the patient was from the Aurum or GOLD cohort and calculated hazard ratios with adjustments for inverse probability of treatment weights.Cox regression assumes proportional hazards-that is, the relative hazard of the outcome remains constant during the follow-up period. 66e assessed this assumption using the Grambsch-Therneau test based on the Schoenfeld residuals. 67ecause this assumption did not hold for all outcomes examined, in addition to reporting the hazard ratios pertaining to the whole follow-up period, we estimated hazard ratios separately for the several time windows: the first seven days, 8-30 days, 31-180 days, 181-365 days, and 366 days to two years (see supplementary appendix for an illustration of stratification of followup time).For each outcome, we calculated the incidence rate and the number needed to harm (NNH) over the first 180 days as well as two years after start of followup.The NNH represents the number of patients needed to be treated with an antipsychotic for one additional patient to experience the outcome compared with no treatment.We also calculated cumulative incidence percentages (absolute risks) for each outcome accounting for competing mortality risks based on previous recommendations. 68These were calculated at 90 days, 180 days, 365 days, and two years after start of follow-up for antipsychotic users and their matched comparators separately.We also reported the difference in cumulative incidence between antipsychotic users and their matched comparators at these time points.Analyses were conducted using Stata/MP v16.1.

Sensitivity analyses
We investigated two other definitions of antipsychotic use as sensitivity analyses: the first 60 days as current use followed by 120 days of recent use, and a current use period of 30 days followed by a recent use period of 60 days.We also conducted the following post hoc sensitivity analyses.Firstly, as levomepromazine is often prescribed in palliative care to treat distressing symptoms in the last days of life, 69 we censored individuals at the time of their first levomepromazine prescription.
Secondly, we used Fine-Gray subdistribution hazard regression models to estimate the hazard of each adverse outcome, accounting for the competing risks of death. 70These results were reported as subhazard ratios.Thirdly, we compared the incidence rates and hazards of adverse outcomes for male versus female individuals.For these sex specific analyses, we modified the existing matched cohort by excluding non-user comparators who were of a different sex from the antipsychotic user to whom they were matched.We then derived a new propensity score for each individual by excluding sex as a covariate in the propensity score models.Incidence rate ratios and corresponding 95% confidence intervals (CIs) for male versus female individuals were calculated using the 'iri' command in Stata.To investigate whether hazards of each adverse outcome associated with antipsychotic use differed by sex, we fitted Cox regression models with sex, antipsychotic use, and their interaction as covariates.Sex specific hazard ratios and ratios of male to female hazard ratios were reported.

Patient and public involvement
This study is part of a National Institute of Health and Care Research funded programme (RP-PG-1214-20012): Avoiding patient harm through the application of prescribing safety indicators in English general practices (PRoTeCT).Two patient and public involvement members in the project team contributed to the study design and protocol of this study.Our study was not, however, coproduced with people with dementia or their carers.

Characteristics of study population
A total of 173 910 adults (63.0%women) with dementia were eligible for inclusion in the study: 139 772 (62.9% women) in the Aurum dataset and 34 138 (63.4% women) in GOLD.The mean age at dementia diagnosis for individuals in both cohorts was 82.1 years (standard deviation (SD) 7.9 years), and the median age was 83 years (interquartile range (IQR) 78-88 years in Aurum and 78-87 years in GOLD).A total of 35 339 individuals (62.5% women; 28 187 in Aurum, 62.6% women; 7152 in GOLD, 62.5% women) were prescribed an antipsychotic during the study period, and a matched set was generated for each of these individuals.The mean number of days between first dementia diagnosis and date of a first antipsychotic prescription was 693.8 ((SD 771.1), median 443 days) in Aurum and 576.6 ((SD 670.0), median 342 days) in GOLD.A total of 544 203 antipsychotic prescriptions (433 694 in Aurum, 110 509 in GOLD) were issued, of which 25.3% were for a typical antipsychotic and 74.7% for an atypical antipsychotic.The most prescribed antipsychotics were risperidone (29.8% of all prescriptions), quetiapine (28.7%), haloperidol (10.5%), and olanzapine (8.8%), which together accounted for almost 80% of all prescriptions (see supplementary table S1).
Since we excluded people with a history of the event before the start of follow-up, the number of individuals and matched sets included in analysis varies by outcome.Table 1 shows the baseline characteristics of patients for the analysis of stroke, before and after inverse probability of treatment weighting.Antipsychotic users were more likely than their matched comparators to have a history of serious mental illness and to be prescribed antidepressants or benzodiazepines in the 12 months before start of follow-up.After inverse probability of treatment weighting, standardised differences were <0.1 for all covariates.Baseline characteristics of individuals included in the analyses of other outcomes were similar to those reported for stroke (see supplementary tables S2-S9). (Continued)

Incidence rates and relative hazards of adverse outcomes All antipsychotics
In the two years after initiation of antipsychotics, the highest incidence rates of adverse outcomes were for pneumonia, fracture, and stroke, and ventricular arrhythmias were rare (table 2). Figure 1  antipsychotic use (ie, in the 180 days after current use ended) was also associated with increased risk for these outcomes, as well as for fracture, but past use of antipsychotics (ie, after recent use ended) was not associated with increased risks of the adverse outcomes examined, except for pneumonia.For the negative control outcome (appendicitis and cholecystitis), no significant associations were found with current, recent, or any antipsychotic use, but a statistically significant association was observed with past use (1.90, 1.01 to 3.56).
Table 2 shows that the NNH ranged from 9 (95% CI 9 to 10) for pneumonia to 167 (116 to 301) for myocardial infarction during the first 180 days after initiation of antipsychotics, and from 15 (14 to 16) for pneumonia to 254 (183 to 413) for myocardial infarction after two years.These figures suggest that over the 180 days after drug initiation, use of antipsychotics might be associated with one additional case of pneumonia for every nine patients treated, and one additional case of myocardial infarction for every 167 patients treated.At two years, there might be one additional case of pneumonia for every 15 patients treated, and one additional case of myocardial infarction for every 254 patients treated.
Table 3 shows hazard ratios stratified by follow-up time (except for ventricular arrhythmia and the negative control where the number of patients was very low).For almost all outcomes, relative hazards were highest in the first seven days after initiation of antipsychotic treatment.Risks for pneumonia were particularly increased in the first seven days (9.99, 8.78 to 11.40) and remained substantial afterwards (3.39, 3.04 to 3.77, 8-30 days).No increased risks for heart failure were found for current users after 180 days from start of treatment, nor for myocardial infarction one year after drug initiation.However, risks for stroke, venous thromboembolism, fracture, pneumonia, and acute kidney injury remained increased among continuous antipsychotic users up to two years after initiation of treatment.

Types of antipsychotics
During the current use period of 90 days after a prescription, both typical and atypical antipsychotics were associated with increased risks of all adverse outcomes compared with non-use, except for ventricular arrhythmia and the negative control (see supplementary table S10).Hazards were higher when current use of typical antipsychotics was directly compared with atypical antipsychotics for stroke (1.23, 1.09 to 1.40), heart failure (1.18, 1.01 to 1.39), fracture (1.22, 1.08 to 1.38), pneumonia (1.92, 1.77 to 2.08), and acute kidney injury (1.22, 1.05 to 1.42), but no significant differences between the two types of drug were found for the risks of venous thromboembolism or myocardial infarction.
Supplementary table S11 shows the risks of adverse outcomes associated with haloperidol (the most prescribed typical antipsychotic) and with risperidone and quetiapine (the two most prescribed atypical antipsychotics).Current use of risperidone and haloperidol compared with non-use was associated with increased risks of all adverse outcomes except for ventricular arrhythmia and the negative control.Current use of quetiapine compared with non-use was associated with increased risks for fracture, pneumonia, and acute kidney injury.Among current users of haloperidol or risperidone, risks for fracture, pneumonia, and acute kidney injury were higher for haloperidol versus risperidone, but risks for stroke,

Absolute risks of adverse outcomes
Cumulative incidence for all outcomes examined was higher for antipsychotic users versus matched comparators, except for ventricular arrhythmia and the negative control (table 4).The absolute risk, as well as risk difference, was particularly large for pneumonia.In the 90 days after initiation of an antipsychotic, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (95% CI 4.26% to 4.71%) v 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%).At one year, this increased to 10.41% (10.05% to 10.78%) for antipsychotic users compared with 5.63% (5.55% to 5.70%) for non-users (difference 4.78%, 4.41% to 5.16%).

Sensitivity analyses
Similar results were found in sensitivity analysis using two other definitions of antipsychotic use (see supplementary figures S4 and S5).Of the 544 203 antipsychotic prescriptions issued, 1.3% were for levomepromazine (see supplementary table S1).Results remained similar when patients were censored at the time of their first levomepromazine prescription (see supplementary figure S6).Results of the Fine-Gray models accounting for the competing risks of death also showed broadly similar patterns of hazards to those from the Cox models (see supplementary table S12 and figure S7).Sex specific analyses showed that male patients had higher incidence rates of all adverse outcomes than female patients, except for fracture and venous thromboembolism where incidence was higher for female patients than for male patients (see supplementary table S13).Compared with female antipsychotic users, male users had increased hazards for pneumonia and acute kidney injury (male to female hazard ratio 1.16, 95% CI 1.08 to 1.25 for pneumonia and 1.22, 1.08 to 1.37 for acute kidney injury), but lower hazards for stroke (0.81, 0.73 to 0.91).No significant differences were found by sex in the hazards for venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, or fracture (see supplementary table S14).

Discussion
In this population based cohort study of adults (≥50 years) with dementia, use of antipsychotics compared and meta-analyses of studies not limited to patients with dementia have also reported inconsistent evidence for myocardial infarction, or lack of robustness of these data. 33 34 71Our findings for myocardial infarction were similar to those in a study that first documented a modest and time limited increase in risk of this outcome associated with antipsychotic use among patients with dementia. 56In a study of nursing home residents in the US, users of typical, but not atypical, antipsychotics were more likely than non-users to be admitted to hospital for ventricular arrhythmia or cardiac arrest, 35 and a study not limited to older people reported increased risks for ventricular arrhythmia or sudden cardiac death associated with both typical and atypical antipsychotics. 36We did not find any association with ventricular arrhythmia, but the number of events was low and we did not examine cardiac arrest or sudden death.
Increased risks of venous thromboembolism associated with antipsychotic use have been reported in the general population, 38 but meta-analyses found increased risks of venous thromboembolism only among younger users. 39 40Our findings are consistent with those of the Welsh study, which reported increased risks of venous thromboembolism in the 12 months after drug initiation (prior event rate ratio 1.95, 95% CI 1.83 to 2.0). 37In absolute terms, however, these risks were relatively low compared with other outcomes examined in this study.
We found that both the relative and the absolute risks for pneumonia were highest among all outcomes examined.Current users of antipsychotics had a twofold increased risk compared with non-users (fig 1), and although this magnitude of increased risk was comparable to previous reports, 14 31 32 we additionally observed that risks were greater in the first week after drug initiation.One study also reported a particularly high risk for patients with hospital diagnosed pneumonia in the first week, but the magnitude of increase (odds ratio 4.5, 95% CI 2.8 to 7.3) was much lower than our observation. 30he mechanisms linking antipsychotic use and development of pneumonia is not well understood, and substantial heterogeneity exists among the drug substances, but antipsychotic induced extrapyramidal symptoms, sedation, xerostomia (dry mouth), and dyskinesia or impaired swallowing are commonly considered as potential risk factors. 72In addition, because elderly people with pneumonia may be less likely than younger patients to present with respiratory symptoms but more likely to show signs of delirium, 73 it is possible that reverse causality might have contributed to the high risks observed in the early days after drug initiation, as delirium from the onset of pneumonia might have been treated with antipsychotics before pneumonia was diagnosed. 30owever, although causality cannot be inferred, the particularly high increased risks observed for a range of outcomes and not only for pneumonia in the early days after drug initiation are consistent with other studies. 28his could be partly explained by further prescriptions being given only to patients who tolerated the first days of drug use.
5][46] Two studies reported significantly increased risks in users compared with non-users in the 90 days after initiation of atypical antipsychotics. 44 45In contrast, another study observed no increased risks from use of the broad category of atypical antipsychotics, although a significantly increased risk was found with olanzapine. 46In our study, we found increased risks of acute kidney injury with both typical and atypical antipsychotics, with risks being higher for haloperidol than for risperidone and quetiapine.
In a meta-analysis of observational studies, antipsychotic use was associated with increased risks of hip fracture among people with dementia. 41A selfcontrolled case series study of older adult patients (≥65 years) also reported increased risks of falls and fracture after initiation of antipsychotics, but incidence was found to be even higher in the 14 days before treatment started. 43Similar findings were also reported in another study, suggesting that the risks observed during the treatment periods might not be attributable to the antipsychotics alone. 42Although we cannot eliminate confounding in our study, we minimised this risk by adjusting for a large number of both clinical and non-clinical characteristics that might have influenced treatment assignment.We also found no increased risks associated with current or recent antipsychotic use for the negative control outcome (appendicitis and cholecystitis).
Our study found that the risks of stroke and heart failure were higher for typical antipsychotics than for atypical antipsychotics, but risks of venous thromboembolism and myocardial infarction were similar between the two drug classes.We also found no significant differences between haloperidol and risperidone in risks of these four outcomes, but significantly increased risks for stroke, venous thromboembolism, and heart failure for haloperidol versus quetiapine.Previous studies of elderly patients have reported similar risks for cardiovascular or cerebrovascular events associated with use of typical and atypical antipsychotics, 17 74-76 but risks of these outcomes and of all cause mortality were increased with haloperidol versus risperidone. 21 76For fracture and pneumonia, we found that risks were higher in association with typical antipsychotics than atypical antipsychotics and for haloperidol versus risperidone or quetiapine.The findings from previous studies comparing these risks by antipsychotic types have been inconsistent. 30-32 74 75rengths and limitations of this study A key strength of this study was the investigation of a wide range of adverse events in a large population based cohort, and the reporting of both relative and absolute risk differences over multiple periods.Previous studies commonly focused on a single outcome or type of outcome, such as cerebrovascular events, and on the reporting of relative risks.By examining the same cohort at risk, we were able to directly compare the hazards of multiple outcomes without differential biases between the cohorts.In addition, we only included patients with a clinician recorded diagnosis of dementia, and we adjusted for many variables that might have influenced the probability of antipsychotic initiation, seeking to minimise confounding by indication.][49] The database includes all prescriptions issued in participating primary care practices in the UK, and it is recognised as a high quality resource to support international pharmacovigilance. 77The longitudinal nature of CPRD, with linked data from secondary care and mortality records, enabled us to capture the study outcomes from multiple sources, as well as information on prescribing and comorbidities. 78 79Our findings were also robust to different classifications of usage periods and we found no associations between current and recent antipsychotic use with the development of the negative control outcome (appendicitis and cholecystitis).However, a significant association with past use was observed that we are unable to explain.
As with all observational studies, residual confounding cannot be excluded.For example, polypharmacy is common among elderly people, which could lead to drug-drug interactions and potentially confound our findings. 80 81We also did not have information on indications for antipsychotics treatment.We minimised the risk of confounding using propensity score methods to control for imbalances in measurable patient characteristics between antipsychotic users and their matched comparators.However, unlike randomised control trials, which, if properly conducted, could account for both observed and unobserved differences between treated and untreated groups, the propensity score method can only adjust for the observed differences between two groups.Additionally, our choice of covariates was based on the literature and discussions with clinical experts and was not formally structured using, for example, a directed acyclic graph.Although the strong associations with pneumonia in the first seven days of antipsychotic initiation may partially be attributed to reverse causality, however, it is less likely to explain associations over longer periods.We also found no increased risk for appendicitis and cholecystitis during current and recent use-our negative control outcome that was included to detect potential unmeasured confounding. 53Another limitation of our study is that although prescriptions issued in primary care are reliable in CPRD, information on dosage is not well recorded and information on drug adherence or prescriptions issued while patients are in hospital is not available. 48Misclassification of drug use is therefore a potential problem.As with other electronic health data that are routinely collected for administrative rather than research purposes, potential issues exist with coding errors, missing or incomplete information, and variations in data quality between practices and healthcare settings.Although the data undergo quality checks before being released and our use of the linked data would have helped to deal with such problems, we were restricted to data coded in patients' electronic health records.In addition, despite the representativeness of the CPRD data, care should be taken in making inferences beyond the population studied.Our sex specific investigations were also conducted as post hoc analyses.By using existing matched sets but restricting the comparators to those of the same sex as the antipsychotic user to whom they were matched, the number of comparators was greatly reduced.Although we found some evidence of differences in hazards for stroke, pneumonia, and acute kidney injury between male and female antipsychotic users, further research is needed to validate these findings.

Policy implications
The mechanisms underlying the links between antipsychotics and the outcomes in our study are not fully understood.In the UK, US, and Europe, current regulatory warnings for using antipsychotics to treat behavioural and psychological symptoms of dementia were mostly based on evidence of increased risks for stroke and mortality. 8 11 22-26We found a considerably wider range of harms associated with antipsychotic use in people with dementia, and the risks of harm were highest soon after initiation.Our findings must be seen in the context of trial evidence of at best modest benefit on behavioural and psychological symptoms of dementia.][84][85] Atypical antipsychotics, including risperidone, which is one of two antipsychotics licensed in the UK for the treatment of behavioural and psychological symptoms of dementia, have the strongest evidence base, but the benefits are only modest. 82 85ny potential benefits of antipsychotic treatment therefore need to be weighed against the risk of serious harm across multiple outcomes.Although there may be times when an antipsychotic prescription is the least bad option, clinicians should actively consider the risks, considering patients' pre-existing comorbidities and living support.The NNH reported in this study can help to inform clinical judgements on the appropriateness of treatments, taking account of the modest potential benefits reported in clinical trials.When prescriptions of such drugs are needed, treatment plans should be reviewed regularly with patients and their carers to reassess the need for continuing treatment. 9In addition, given the higher risks of adverse events in the early days after drug initiation, clinical examinations should be taken before, and clinical reviews conducted shortly after, the start of treatment.Our study reaffirms that these drugs should only be prescribed for the shortest period possible. 9Although regulators have made efforts to limit the use of these drugs to people with the most severe behavioural and psychological symptoms of dementia, 8 82 86 antipsychotic prescribing in dementia remains common and has even increased in recent years. 4 5 87 88If such trends continue, further communication on the associated risks could be considered by guideline developers or regulators after a review of the totality of evidence.Greater accountability and monitoring in the use of these drugs may be called for, and additional legal reforms may be required to regulate adherence. 89In recent years, other psychotropic drugs such as antidepressants, benzodiazepines, mood stabilisers, and anticonvulsants have been prescribed instead of antipsychotics for the treatment of behavioural and psychological symptoms of dementia. 28 90 91These drugs, however, also pose their own risks.Further research is needed into safer drug treatment of behavioural and psychological symptoms of dementia and more efficacious, easy to deliver, initial non-drug treatments.

Conclusions
Antipsychotic use is associated with a wide range of serious adverse outcomes in people with dementia, with relatively large absolute risks of harm for some outcomes.These risks should be considered in future regulatory decisions, alongside cerebrovascular events and mortality.Any potential benefits of antipsychotic treatment need to be weighed against risk of serious harm, and treatment plans should be reviewed regularly.The effect of antipsychotics on behavioural and psychological symptoms of dementia is modest at best, but the proportion of people with dementia prescribed antipsychotics has increased in recent years.Our finding that antipsychotics are associated with a wider range of risks than previously known is therefore of direct relevance to guideline developers, regulators, and clinicians considering the appropriateness of antipsychotic prescribing for behavioural and psychological symptoms of dementia.

Fig 1 |
Fig 1 | Hazard ratios (adjusted for inverse probability of treatment weights) of adverse outcomes associated with current, recent, and past antipsychotic use; with current use being defined as the first 90 days from the date of an antipsychotic prescription, recent use as up to 180 days after current use ended, and past use as after recent use.CI=confidence interval

Table 1 |
Baseline characteristics of antipsychotic users and matched comparators included in the analysis of stroke (CPRD Aurum and GOLD combined data).Values are number (percentage) unless stated otherwise See supplementary tables S2 to S9 for baseline characteristics for other outcomes.ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; COPD=chronic obstructive pulmonary disease; CPRD=Clinical Practice Research Datalink; IPT=inverse probability of treatment; NSAID=non-steroidal anti-inflammatory drug; SD=standard deviation.*History of the condition.

Table 2 |
Incidence rate (per 10 000 person years) and number needed to harm of adverse outcomes associated with antipsychotic use during the first 180 days and two years of follow-up period CI=confidence interval; NA=not applicable; NNH=number needed to harm.*Appendicitis and cholecystitis.†No significant difference between incidence rate for antipsychotic users and incidence rate for matched comparators.the bmj | BMJ 2024;385:e076268 | doi: 10.1136/bmj-2023-076268 on 21 April 2024 by guest.Protected by copyright.

Table 3 |
Hazard ratios (adjusted for IPT weights) of adverse outcomes associated with current, recent, and past antipsychotic use stratified by follow-up period Current use is defined as the first 90 days from the date of an antipsychotic prescription, recent use as up to 180 days after current use ended, and past use as after recent use (not reported for ventricular arrhythmia and negative control outcome (appendicitis and cholecystitis) because of small numbers).CI=confidence interval; IPT=inverse probability of treatment.the bmj | BMJ 2024;385:e076268 | doi: 10.1136/bmj-2023-076268 on 21 April 2024 by guest.Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj-2023-076268 on 17 April 2024.Downloaded from